1) Field of the Invention
The present invention relates to novel caffeic acid derivatives, and more specifically to novel caffeic acid derivatives having 12-lipoxygenase inhibitory action and useful for the prevention and treatment of diseases of the circulatory system, such as arteriosclerosis, and medicines containing the derivatives as effective ingredients.
2) Description of the Related Art
Leukotriene which is considered to be a cause for allergic diseases, especially for asthma is known to be formed in the course of the conversion of arachidonic acid to 5-hydroperoxyeicosatetraenoic acid (5-HPETE) and 5-hydroxyeicosatetraenoic acid (5-HETE) under the action of 5-lipoxygenase.
Based on the findings, compounds having 5-lipoxygenase inhibition activity have been investigated with a view toward developing therapeutic agents for diseases of the circulatory system, resulting in many reports.
On the other hand, it is also known that 12-hydroperoxyeicosatetraenoic acid (12-HPETE) and 12-hydroxyeicosatetraenoic acid (12-HETE) are formed from arachidonic acid by another enzyme, 12-lipoxygenase. Regarding effects of these products on organisms, there are the report by Tada et al. that 12-HETE takes part in the development of ischemic heart disease [Cardiovascular Research, 21(8), 551-558 (1987] and the report by Murota et al. that 12-HETE exhibits deteriorating action for endothelial cell diseases and wandering stimulating action for vascular tunica media smooth muscle cells and takes part in the increase and deterioration of vascular diseases such as arteriosclerosis and nephritis [Chiryogaku (Therapy), 13(6), 785-788 (1984)]. From the above findings, compounds having 12-lipoxygenase inhibitory action are expected to have utility as therapeutic agents for diseases of the circulatory system.
Compounds conventionally known to have 12-lipoxygenase inhibitory action include baicalein isolated from Scutellaria baicalensis and represented by the following formula: ##STR2##
Although baicalein has 12-lipoxygenase inhibitory action, it is difficult to obtain it in large quantity as it is a natural product. Baicalein is therefore not suited for use as a medicine, leading to a desire for the development of a new inhibitor which can be produced by chemical synthesis.
With the foregoing in view, Cho, Murota and others--inventors of the present invention--have synthesized a variety of compounds and investigated their pharmacological effects. As a result, it was found that some of the compounds have 12-lipoxygenase inhibitory action. Some patent applications have already been filed on such compounds (Japanese Patent Application Laid--Open No. 275552/1989, Japanese Patent Application No. 55867/1989, etc.).